Abstract：
Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.
摘要：
遗传镶嵌一直与衰老有关，并且已经提出了一些假设来解释镶嵌和癌症易感性之间的潜在联系。已经提出镶嵌可能通过影响细胞间通讯和释放组织内的微环境约束来破坏组织稳态。驱动这些组织水平影响的潜在机制尚未确定，however.这里,我们提出了一个关于镶嵌和癌症之间相互作用的进化观点，这表明遗传镶嵌的组织水平影响可归因于间接遗传效应(IGEs)。IGEs可以增加相邻细胞之间的细胞随机性和表型不稳定性的水平，从而提高组织内癌症发展的风险。此外，当细胞经历表型变化以应对具有挑战性的微环境条件时，这些变化可以引发一系列非遗传改变，称为间接非遗传效应(InGEs)，反过来催化周围细胞之间的IGE。我们认为，将InGE和IGE纳入我们对致癌转化过程的理解可能会引发癌症研究的重大范式转变，对实际应用具有深远的意义。
